| Structural highlights
Function
[RBM5_HUMAN] Component of the spliceosome A complex. Regulates alternative splicing of a number of mRNAs. May modulate splice site pairing after recruitment of the U1 and U2 snRNPs to the 5' and 3' splice sites of the intron. May both positively and negatively regulate aopotosis by regulating the alternative splicing of several genes involved in this process, including FAS and CASP2/caspase-2. In the case of FAS, promotes exclusion of exon 6 thereby producing a soluble form of FAS that inhibits apoptosis. In the case of CASP2/caspase-2, promotes exclusion of exon 9 thereby producing a catalytically active form of CASP2/Caspase-2 that induces apoptosis.[1] [2] [3] [4] [5] [6] [7]
Publication Abstract from PubMed
The multi-domain splicing factor RBM5 regulates the balance between antagonistic isoforms of the apoptosis-control genes FAS/CD95, Caspase-2 and AID. An OCRE (OCtamer REpeat of aromatic residues) domain found in RBM5 is important for alternative splicing regulation and mediates interactions with components of the U4/U6.U5 tri-snRNP. We show that the RBM5 OCRE domain adopts a unique beta-sheet fold. NMR and biochemical experiments demonstrate that the OCRE domain directly binds to the proline-rich C-terminal tail of the essential snRNP core proteins SmN/B/B'. The NMR structure of an OCRE-SmN peptide complex reveals a specific recognition of poly-proline helical motifs in SmN/B/B'. Mutation of conserved aromatic residues impairs binding to the Sm proteins in vitro and compromises RBM5-mediated alternative splicing regulation of FAS/CD95. Thus, RBM5 OCRE represents a poly-proline recognition domain that mediates critical interactions with the C-terminal tail of the spliceosomal SmN/B/B' proteins in FAS/CD95 alternative splicing regulation.
Structural basis for the recognition of spliceosomal SmN/B/B' proteins by the RBM5 OCRE domain in splicing regulation.,Mourao A, Bonnal S, Soni K, Warner L, Bordonne R, Valcarcel J, Sattler M Elife. 2016 Nov 29;5. pii: e14707. doi: 10.7554/eLife.14707. PMID:27894420[8]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Sutherland LC, Edwards SE, Cable HC, Poirier GG, Miller BA, Cooper CS, Williams GT. LUCA-15-encoded sequence variants regulate CD95-mediated apoptosis. Oncogene. 2000 Aug 3;19(33):3774-81. PMID:10949932 doi:http://dx.doi.org/10.1038/sj.onc.1203720
- ↑ Mourtada-Maarabouni M, Sutherland LC, Williams GT. Candidate tumour suppressor LUCA-15 can regulate multiple apoptotic pathways. Apoptosis. 2002 Oct;7(5):421-32. PMID:12207175
- ↑ Mourtada-Maarabouni M, Sutherland LC, Meredith JM, Williams GT. Simultaneous acceleration of the cell cycle and suppression of apoptosis by splice variant delta-6 of the candidate tumour suppressor LUCA-15/RBM5. Genes Cells. 2003 Feb;8(2):109-19. PMID:12581154
- ↑ Rintala-Maki ND, Sutherland LC. LUCA-15/RBM5, a putative tumour suppressor, enhances multiple receptor-initiated death signals. Apoptosis. 2004 Jul;9(4):475-84. PMID:15192330 doi:http://dx.doi.org/10.1023/B:APPT.0000031455.79352.57
- ↑ Oh JJ, Razfar A, Delgado I, Reed RA, Malkina A, Boctor B, Slamon DJ. 3p21.3 tumor suppressor gene H37/Luca15/RBM5 inhibits growth of human lung cancer cells through cell cycle arrest and apoptosis. Cancer Res. 2006 Apr 1;66(7):3419-27. PMID:16585163 doi:http://dx.doi.org/66/7/3419
- ↑ Bonnal S, Martinez C, Forch P, Bachi A, Wilm M, Valcarcel J. RBM5/Luca-15/H37 regulates Fas alternative splice site pairing after exon definition. Mol Cell. 2008 Oct 10;32(1):81-95. doi: 10.1016/j.molcel.2008.08.008. PMID:18851835 doi:http://dx.doi.org/10.1016/j.molcel.2008.08.008
- ↑ Fushimi K, Ray P, Kar A, Wang L, Sutherland LC, Wu JY. Up-regulation of the proapoptotic caspase 2 splicing isoform by a candidate tumor suppressor, RBM5. Proc Natl Acad Sci U S A. 2008 Oct 14;105(41):15708-13. doi:, 10.1073/pnas.0805569105. Epub 2008 Oct 7. PMID:18840686 doi:http://dx.doi.org/10.1073/pnas.0805569105
- ↑ Mourao A, Bonnal S, Soni K, Warner L, Bordonne R, Valcarcel J, Sattler M. Structural basis for the recognition of spliceosomal SmN/B/B' proteins by the RBM5 OCRE domain in splicing regulation. Elife. 2016 Nov 29;5. pii: e14707. doi: 10.7554/eLife.14707. PMID:27894420 doi:http://dx.doi.org/10.7554/eLife.14707
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